DK162892B - 1,2,5,6-TETRAHYDROPYRIDINE COMPOUNDS, THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE - Google Patents

Description

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DK 162892B

The invention relates to novel therapeutically active 1,2,5,6-tetrahydropyridine compounds, a method of preparing the same and pharmaceutical compositions containing the compounds. The novel compounds of the invention are useful as stimulants of the cognitive function of the forebrain and hippocampus in mammals and in particular in the treatment of Alzheimer's disease.

Due to the generally increased public health in the Western world, age-like diseases are considerably more common now than in the past and are likely to be even more common in the future.

One of the age-related symptoms is a reduction in cognitive functions. This symptom is particularly pronounced in the pathophysiological Alzheimer's disease. This disease is accompanied by, and probably also caused by, up to 90% degeneration of the muscarinic cholinergic neurons in the nucleus basalis, which is part of the substantia innominata. These neurons 25 project to the prefrontal cortex and hippocampus and have a generally stimulating effect on the cognitive functions of the forebrain as well as in the hippocampus, namely learning, association, consolidation and recall.

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It is characteristic of Alzheimer's disease that although the cholinergic neurons degenerate, the post-synaptic muscarinic receptors in the forebrain and hippocampus still exist. Therefore, muscarinic cholinergic agonists are useful in the treatment of Alzheimer's disease and in increasing the cognitive functions of the elderly.

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It is well known that arecoline (methyl 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate) is such a cholinergic agonist.

However, Arecolin has a very short biological half-life and a small separation between central and peripheral muscarinic effects. Furthermore, arecoline is a rather toxic compound.

Danish Patent Application No. 1542/87 discloses 1,2,5,6-tetrahydropyridine derivatives which, in the 3-position of the tetrahydropyridine ring, are substituted with a 1,2,4-oxadiazolyl group. These compounds are said to have ». ,; , effect, especially in the treatment of Alzheimer's disease.

It is therefore an object of the present invention to find new muscarinic cholinergic compounds.

The novel compounds of the invention have the general formula I: Wherein R 1 is H or C 1-6 alkyl and R 1 is hydrogen, alkyl, C 1-6 cycloalkyl, C 1-4 alkoxy, C 2-8 alkenyl or C 2-6 alkynyl or a salt thereof with a pharmaceutically acceptable acid .

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Examples of such salts include inorganic and organic acid addition salts such as the hydrochloride, hydrobromide, sulfate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically acceptable inorganic or organic acid addition salts.

The present compounds of formula I can be prepared by a process comprising reacting a reactive derivative of a compound of formula II

(ID

tf 20 where R1 has the meaning defined above.

The pharmacological properties of the compounds of the invention can be illustrated by determining their ability 3 to inhibit the specific binding of H-Oxotremorin-M 25 (3H-Oxo).

3H-0xo labels muscarinic receptors in the CNS (with preference for agonist receptor regions). Three different areas are marked by 3H-0xo. These areas have an affinity of respectively. 1.8, 20 and 3000 nM. When the experimental conditions mentioned are used, only high and medium affinity ranges are determined.

The inhibitory effect of the compounds on 3H-Oxo binding 35 reflects their affinity for muscarinic acetylcholine receptors.

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All steps in the test procedure are performed at 0-4 ° C unless otherwise indicated. Fresh cortex (0.1-1 g) from male Wistar rats (150-250 g) is homogenized for 5-10 sec. in 10 ml of 20 mM Hepes pH: 7.4, with an Ultra-Turrax 5 homogenizer. The homogenizer is purified with 10 ml of buffer and the total suspension is centrifuged for 15 min. at 40,000 x g. The precipitate is washed three times with buffer. In each step, the precipitate is homogenized as before in 2x10 ml buffer and centrifuged for 10 min. at 40,000 χ g.

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The final precipitate is homogenized in 20 mM Hepes pH: 7.4 (100 ml per g of original tissue) and used for binding experiments. 0.5 ml aliquots are added to 25 μΐ of test solution and 25 μΐ of 3 H-Oxotremorine (1.0 nM, final concentration) mixed and incubated for 30 min. at 25 ° C.

Non-specific binding is determined three times using Arecolin (1 µg / ml, 'final concentration) as the test substance'. After incubation, the samples are added 5 ml of ice-cold buffer and poured directly onto Whatman GF / C fiberglass filter under suction and washed immediately twice with 5 ml of ice-cold buffer; The amount of radioactivity on the filters is determined by conventional liquid scintillation counting. Specific binding is total binding minus non-specific binding.

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The test compounds are dissolved in 10 rals of water (if necessary heated in a steam bath for less than 5 minutes) to a concentration of 2.2 mg / ml. 25-75% inhibition of specific binding must be achieved before calculating IC

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The test value will be given as IC ^ q (concentration (ng / ml) of the test compound which inhibits the specific binding of 3H-Oxo by 50%).

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ICgQ * (test substance concentration used) x - ng / ml r co i - - 1 5 L Cx where CQ is the specific binding in the control experiment and C is the specific binding in the test experiment (

X

10 assumes normal mass action kinetics).

Test results obtained by testing certain compounds of the invention are shown in the following table: TABLE 1

Compound Inhibition 20 of the In Vitro Invention Oxo-Bond (ng / ml)

Compound 1 1.6 25

Compound 2 11 30

The compound of the invention, together with a traditional adjuvant, carrier or diluent, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof, can be formed into pharmaceutical compositions and unit doses thereof, and may be administered

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6, such form is used as solid materials, such as tablets or filled capsules, or as liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all intended for oral use, or they can be prepared for rectal suppositories administration or in the form of sterile injectable parenteral solutions (including subcutaneous applications). Such pharmaceutical preparations and unit dosage forms thereof may comprise conventional ingredients in conventional amounts, with or without additional active compounds or principles, and such unit dosage forms may contain any conveniently effective muscarinic cholinergic agonist amount of the active compound corresponding to the daily compound. 15 equal dose, it is intended to be used. Tablets containing ten (10) milligrams of the active compound or, more broadly, ten (10) to one hundred (100) milligrams per tablet, represent appropriate representative unit dosage forms.

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Thus, the compounds of the invention can be used to formulate pharmaceutical compositions, e.g. for oral or parenteral administration to mammals, including humans, by methods well known in the art of galenic pharmacy.

Conventional additives are such pharmaceutically acceptable organic or inorganic carriers suitable for parenteral or enteral administration which do not adversely react. the active compounds.

Examples of such carriers are water, saline, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid,

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hydroxymethyl cellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired, with adjuvants, lubricants, salts affecting the osmotic pressure, buffers, and / or dyes and the like, which do not adversely react with the active compounds.

For parenteral use, injectable solutions 10 or suspensions are preferably aqueous solutions of the active compound dissolved in polyhydroxylated castor oil, especially suitable.

Ampoules are appropriate unit doses.

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Tablets, dragons, or capsules with talc and / or carbohydrate carrier or binder or the like, preferably lactose and / or corn starch and / or potato starch, are particularly suitable for oral use. A syrup, elixir or the like can be used in cases where a sweetened carrier is used.

Generally, the compounds of the invention are dispensed in unit dosage form containing 1-100 mg in a pharmaceutically acceptable carrier per unit dose.

The dosage of the compounds of the invention is 1-100 mg / day, preferably 10-70 mg / day, when administered to patients, i.e. people, as a drug.

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A typical tablet which can be prepared by conventional tablet erasing techniques contains: 35

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Active compound 5.0 mg

Lactose 67.8 mg Ph.Eur.

Avicel® 31.4 mg Ph.Eur.

Amberlite® IRP 88 1.0 mg 5 Magnesii stearas 0.25 mg Ph.Eur.

Because of the high muscarinic cholinergic receptor agonistic activity, the compounds of the invention are particularly useful in treating symptoms related to a reduction in the cognitive functions of the mammalian brain when administered in an amount effective to stimulate the mammalian brain. cognitive functions of the forebrain and hippocampus. The important stimulatory activity of the compounds of the invention includes both activity against the pathophysiological disease, Alzheimer's disease, as well as against normal degeneration of brain function. Therefore, the compounds of the invention may be administered to a subject, i.e. a living organism, including a human, in need of stimulation of the cognitive functions of the forebrain and hippocampus, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof (such as the hydrobromide, hydrochloride, or sulfate, in any case prepared in the usual or traditional manner, i.e. by evaporation of the free base in solution with the acid), usually cooperatively, simultaneously; or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical preparation thereof, either by oral, rectal, or parenteral (including subcutaneous) administration in an effective cerebral and hippocampal stimulating amount, and in any case a amount effective to increase the cognitive functions of mammals due to their muscarinic cholinergic receptor 35 agonist activity1 Appropriate dose limits are 1-100 milligrams daily, 10-100 milligrams daily, and especially 30-70 milligrams daily, as usual depending on the * , · .

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exact manner of administration, form of administration, the indication to which the administration is directed, the individual involved and the body weight of the individual involved and the preferences and experiences of the responsible physician 5 or veterinarian.

The invention will now be described in more detail with reference to the following Examples: EXAMPLE 1 a. 1,2,5,6-Tetrahydro-1-methyl-3-pyridinecarbothioamide

A solution of 1,2,5,6-tetrahydro-1-methyl-3-pyridine carboxamide (4.2 g, 30.2 mmol) and Lawesson's reagent (6.1 g, 15.1 mmol) in HMPA ( hexamethylphosphoramide (80 ml) was stirred at 80 ° C for 2.5 hours. After cooling to room temperature, a saturated potassium carbonate solution (100 ml) was added to the reaction mixture. The water / HMPA solution was extracted with ether (3 x 500 ml) and the combined ether phases dried; filtered and evaporated. The residue was chromatographed on silica gel with CH 2 Cl 2: MeOH (9: 1) as eluent. The main peak was the desired product which could be isolated as a yellow solid in 410 mg yield. MS: M + 156 (100%), 123 (90%).

B. 1,2,5,6-Tetrahydro-1-methyl-3- (3-methyl-1,2,4-thia-diazol-5-yl) pyridine oxalate A solution of 1.2, 6-Tetrahydro-1-methyl-3-pyridine carbothioamide (360 mg, 2.3 mmol) in N, N-dimethylacetamide dimethyl acetate (2.5 mL, 17 mmol) was stirred at

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10 room temperature for 3 hours. The reaction mixture was evaporated in vacuo to give a black-brown oil.

After dissolving the residue in EtOH (7 mL, 99.9%) and pyridine (0.18 mL), a solution of 5 hydroxylamine-O-sulfonic acid (283 mg, 2.5 mmol) in MeOH (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and evaporated. The evaporation residue was dissolved in a saturated potassium carbonate solution (5 ml) and extracted with ether (5 x 20 ml). The combined organic phases 10 were dried and evaporated. Chromatographic purification of the residue on silica gel (elution with C

MeOH (9: 1) gave 130 mg of the desired product. HNMR (60 MH 2, CDCl 3): 6.65 (1H, m), 3.35 (2H, s, s), 2.60 (3H, s), 2.42 (3H, s), 2, 8- 2.2 (4H, m). Crystallization with oxalic acid from acetone gave 130 mg of the title compound. Mp. 175-177 ° C. GC / MS: M +: 195 (100%). (Compound 1).

Example 2 a. 3- (1,2,4-Thiadiazol-5-yl) pyridine

A solution of thionicotinamide (10.0 g, 72.5 mmol) in 25 N, N-dimethylformamide dimethyl acetal (51 mL, 359 mmol) was stirred at 90 ° C for 3 hours, followed by 16 hours at room temperature. After evaporation, the brown oil residue was dissolved in ethanol (200 ml) and pyridine (5.7 ml).

A solution of hydroxylamine-O-sulfonic acid (9.75 g, 86 30 mmol) in methanol (90 ml) was added at room temperature and the reaction mixture was stirred for 3 hours. The reaction mixture was evaporated and the residue was dissolved in water. The aqueous phase was extracted with ether after addition of potassium carbonate to pH 10. The combined ether phases were dried and purified by column chromatography with ethyl acetate as eluant. Yield: 1.5 g. M +: 163 (100%).

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11 b. 1,2,5,6-Tetrahydro-1-methyl-3- (1,2,4-thiadiazol-5-yl) pyridine oxalate A solution of 3- (1,2,4-thiadiazole-5) -yl) pyridine (1.5 g, 9.2 mmol) in acetone (50 ml) was added methyl iodide (6 ml, 100 mmol). The reaction mixture was stirred at room temperature for 16 hours and the precipitate was collected by filtration, 1.98 g. The precipitate was dissolved in methanol (50 ml) and cooled to 0 ° C. Sodium borohydride (448 mg, 11.8 mmol) was added to the reaction mixture. After 15 min. at 0 ° C, the reaction mixture was evaporated. The residue was dissolved in water and extracted with ether, dried and evaporated. Crystallization as the oxalate salt from acetone afforded the title compound in 370 mg yield.

Mp. 166-170 ° C decomp. M +: 181. (Compound 2).

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Claims (6)

2. A compound according to claim 1, characterized in that it is 1,2,5,6-tetrahydro-1-methyl-3- (3-methyl-1,2,4-thia-diazol-5-yl) -pyridine. or a salt thereof with a pharmaceutically acceptable acid. A compound according to claim 1, characterized in that it is 1,2,5,6-tetrahydro-3- (1,2,4-thiadiazol-5-yl) -1-methylpyridine or a salt thereof with a pharmaceutically acceptable acid '. 30 ' A method of preparing a compound according to claim 1, characterized by reacting a reactive derivative of a compound of formula II [NT 2 (il) R1 in 10 wherein R has the meaning defined above with a compound of formula III r, -c (och3) 2n (ch3) 2 (III) 15 wherein R 'has the meaning defined above. A pharmaceutical composition, characterized in that it contains a compound according to claims 1-3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition suitable for use in stimulating the cognitive functions of mammals and hippocampus in mammals, including humans, and in the treatment of Alzheimer's disease, containing an amount of a compound according to claims 1-3, which is effective in stimulating the forebrain and hippocampus in mammals or in the treatment of Alzheimer's disease, together with a pharmaceutically acceptable carrier or diluent. Pharmaceutical composition according to claim 5 or 6, characterized in that it is in the form of an oral unit dose containing 1-100 mg of the active compound. DK 162892 B 14 Use of a compound according to claims 1-3 or a pharmaceutical salt thereof for the preparation of a pharmaceutical composition for the treatment of Alzheimer's disease or a pharmaceutical composition effective in stimulating the forebrain and hippocampus of mammals, including humans. 10 20 25 30 35